1. Persistence of Rilpivirine Following Single Dose of Long-Acting Injection Ian McGowan MD DPhil FRCP Professor of Medicine, University of Pittsburgh for the MWRI-01 Team

2. Disclosure I have no financial relationships with a commercial entity producing, marketing, reselling or distributing healthcare related products and/or services.

3. Antiretroviral Persistence  Long acting (LA) injectable antiretrovirals (ARV) are being developed for both treatment and prevention indications  The extended half-life associated with LA- ARV is poorly characterized but may increase the risk of ARV resistance in individuals who seroconvert after exposure to LA PrEP

4. The Pharmacokinetic (PK) Tail Female participant receiving a single 1200 mg dose of rilpivirine (RPV) McGowan I et al. HIVR4P 2014

5. Resistance after Single 300mg Dose of RPV LA Penrose K et al. JID 2016 Time after injection (days)

6. Methods

7. MWRI-01 Study  A Phase 1 safety, acceptability, PK/PD evaluation of RPV LA (TMC278)  Single dose phase  Men and women randomized to receive 600 mg or 1200 mg of TMC278 LA  Multiple dose phase  Men and women received 1200 mg of TMC278 LA

8. Primary Objectives  Primary objective  To evaluate the safety and acceptability of RPV LA given as an intramuscular injection  Primary endpoints  Grade 2 or higher clinical and laboratory adverse events  The proportion of participants who would consider using RPV LA for HIV prevention in the future

9. Secondary Objectives  Secondary objectives  To determine the plasma, cervical, vaginal, and rectal tissue/secretion PK following single and multiple IM injections of RPV LA  Secondary endpoints  RPV concentrations in plasma, cervical, vaginal, and rectal tissue/secretions

10. MWRI-01 Design ScreenBaseline+1 month +2 month +3 month +4 month +5 month +6 month N = 5 N = 4 ♀ ♂ 1200 mg 600 mg 1200 mg 600 mg 1A (N=12) 2A (N=12) 1B (N=6) 2A (N=6) 1200 mg 3A (N=8) 3A (N=4)

11. PK Analysis (1)  RPV concentrations in all matrices were quantified by validated high-pressure liquid chromatography-mass spectrometry  Matrix lower limit of quantification (LLOQ)  Plasma: 0.5 ng/ml  Fluids: 0.025 ng/sample  Tissue: 0.05 ng/sample Else LJ et al. Bioanalysis. 2014

12. PK Analysis (2)  Two blanks (extracted drug-free plasma) were included after the upper limit of quantification (400 ng/ml) and after the MQC/HQC  The % carryover after a single blank sample was <20% of the assay LLQ (0.5 ng/ml)

13. Results

14. Demographics  Baseline samples were available from 9 participants  1200 mg: 5 females and 2 males  600 mg: 2 males

15. Persistence of RPV  RPV was detectable in 7/7 (100%) of plasma samples collected a mean of 541 days after single dose exposure to 1200 mg of RPV LA  RPV was also detected in endocervical and vaginal fluid  No RPV was found in cervical, vaginal, or rectal tissue or cervicovaginal lavage samples

16. Baseline PK 4.1 ± 2.46.1 ± 4.113.2 ± 10.9

17. Time from RPV LA Exposure All Samples1200mg Samples

18. Time from RPV LA Exposure All Samples1200mg Samples

19. Conclusions  Quantifiable RPV was found in plasma and female genital tract fluids > 18 months after single dose administration of RPV LA (Mean plasma level 4.1 ng/mL)  Protein-adjusted RPV EC 90 is 12 ng/mL  Further characterization of LA PrEP extended PK profile will be critical to better inform management of the PK tail to avoid the potential for ARV resistance

20. Acknowledgements  University of Pittsburgh Clinical and Stats Support  Ross Cranston  Beatrice Chen  Sharon Achilles  Ron Stall  Patty Peters  Carol Oriss  Carly Mowry  Carol Mitchell  Jonathan Baker  Stacey Edick  Kaleab Abebe  Cindy Jacobson  University of Pittsburgh Lab Support  Charlene Dezzutti  Kathy Duffill  Aaron Siegel  Jarret Engstrom  Alexyi Nikorov  University of Pittsburgh Recruitment and Project Management Support  Kathy McCarthy  University of Liverpool  David Back  Saye Khoo  Laura Else  Deidre Egan  Janssen R & D  Peter Williams  Marita Stevens  Joseph Mrus  Alpha StatConsult LLC  Nicola Richardson-Harman  Bill & Melinda Gates Foundation  Lut Van Damme

21. Funding for the MWRI-01 Study